Impairment of vocational activities and financial problems are frequent among German blood cancer survivors

Little is known about changes in the personal living conditions of long-term blood cancer survivors in Germany. To gather information about social relationships, work life, overall well-being, and religion, we performed a questionnaire-based retrospective study on 1551 survivors who had been on follow-up for ≥ 3 years (median, 9 years). Most survivors reported that marital status and relationships with relatives and friends remained constant before and after blood cancer. Vocational activities were temporarily impaired for 47.5%, with a median time of 11 months to return to work. More than a third of the patients (35.6%) discontinued work permanently, with disability and retirement pension rates of 7.9% and 38.1%, respectively, at the time of the survey. Financial problems due to reduced income were reported by 26.2%, in particular after relapse or allogeneic transplantation. Patient reports addressing their quality of life showed large variations. It was best in acute leukemia survivors without a history of allogeneic transplantation and worst in patients with myeloproliferative disorders. Religion tended to become more important after blood cancer. In conclusion, vocational impairment and financial problems are frequent among German blood cancer survivors. Efforts should be made at an early stage to reestablish the patients’ ability to work.


Eligibility
The patient eligibility criteria have been previously described 31 .In brief, patients ≥ 18 years diagnosed with and/ or treated for a hematological malignancy at the University Hospital of Essen were eligible for the study, provided that the interval between study inclusion and the date of diagnosis (for untreated patients) or the end of last treatment (for primary disease, relapse, or a second primary malignancy) was ≥ 3 years.In patients receiving continuous oral medication or low dose maintenance therapy after intensive induction, eligibility started 3 years after treatment initiation or end of induction, respectively.Because relapse tends to occur early in hematological malignancies [8][9][10] , initial follow-up is usually provided by the institution where the patient received treatment.Survivors without early relapse may subsequently migrate to other institutions.To be able to compare different institutions we limited the study to survivors with an interval since the last intense treatment of at least 3 years.Patients exclusively treated in childhood or adolescence were not eligible 31 .The term 'blood cancer' encompassed all types of hematological malignancies including leukemias, myelodysplastic syndromes, myeloproliferative diseases, lymphomas, multiple myeloma, and its precursor, monoclonal gammopathy of undetermined significance.In an effort to establish a manageable number of disease categories, characterized by similar treatment approaches and similar prognosis, the diseases were allocated to seven groups: monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), indolent non-Hodgkin lymphoma including chronic lymphocytic leukemia (iNHL/CLL), myeloproliferative neoplasms including chronic myeloid leukemia (MPN/CML), myelodysplastic syndromes (MDS), aggressive non-Hodgkin or Hodgkin's lymphoma (aNHL/HL), and acute myeloid or acute lymphoblastic leukemia (AML/ALL).Irrespective of the underlying disease, patients undergoing allogeneic transplantation were allocated to a separate group (AlloTx), because health issues arising ≥ 3 years after transplantation are more likely to be related to the procedure than to the disease 31 .

Study design
The ABC study was an observational study performed from October 2013 to December 2016.It comprised a retrospective study and an 18-month prospective study 31 .It was performed in line with the principles of the Declaration of Helsinki and approved by the Ethics Committee of the University of Duisburg-Essen (February 17, 2014; no.14-5692-BO).The present manuscript describes the results of a substudy within the retrospective part.All participating patients gave written informed consent.
In the retrospective part of the study, eligible patients were identified by hospital documents spanning the period from 1999 to 2010 31 .The patients were informed by mail about the purpose of the study and invited to complete a 118-item questionnaire specifically designed for the study.Twenty-one questions were related to personal living conditions (see Supplementary Information S1).Quality of life was assessed by the German versions of the EORTC QLQ C-30 and Hospital Anxiety and Depression Scale (HADS) questionnaires.Patients not responding within 4-6 weeks were contacted by mail again, and patients failing to respond to the second invitation were reminded by phone 31 .

Statistical analysis
The analysis focused on three areas: social relationships (seven questions of the questionnaire related to marital status, family, friends and relatives), work life (11 questions related to employment, financial situation, and health insurance), and overall well-being and spirituality (two quality-of life questionnaires, one question related to religion).The analysis included comparisons of the period before and after blood cancer (social relationships, employment, health insurance, religion), comparisons of blood cancer subgroups (financial situation, quality of life), comparisons of survivors with or without disease relapse (financial situation), comparison of different age groups (employment, financial situation), and comparisons of different follow-up periods (4-5, 6-10, < 10 years; quality of life).
The statistical methods employed in the ABC study have been described before 31 .Frequencies are presented as numbers and compared using the chi 2 test.Unless otherwise stated, percentages refer to the total number of patients, i.e., they are not corrected for missing data.Continuous data are presented as median, first and third quartile (interquartile range, IQR), compared using the Kruskal-Wallis test, and graphically displayed as boxwhisker plots, diamonds representing means.All analyses are exploratory, assuming statistical significance at p ≤ 0.05.
The quality-of-life assessment included the broad domains global health, functioning (physical, role, cognitive, emotional, and social combined), and symptoms of the EORTC QLQ C-30 questionnaire and anxiety and depression of the HADS questionnaire.It was restricted to the time of the survey.The following transformations from the log-transform family were found to yield well normalized scales, suitable for analysis of variance (ANOVA) and co-variance (ANCOVA): Note that the sense of direction is maintained, i.e. with increasing X, Y also increases.To adjust the influence of 'disease group' (nominal, p value for group difference) and 'time since last treatment or diagnosis' (ordinal, p value for trend) on the quality-of-life scales for age and sex, the transformed scales were modelled using respective general linear models.

Patients
Of 2555 patients contacted, 841 men and 710 women participated in the study 31 .The median age was 58 years (range, 23-91), the median time from diagnosis was 11 years (range, 3-41), and the median time from last treatment was 9 years (range, 3-36).The survivors were allocated to 7 groups of diseases not treated by allogeneic transplantation, and one allogeneic transplantation group comprising all 554 transplanted patients irrespective of the underlying disease (Table 1).The survivors were asked whether their present living conditions differed from those before the advent of blood cancer.

Marital status
The number of survivors that were married (1118 [72.1%] versus 1089 survivors [70.2%]; p = 0.2505) or were living with a partner (1205 [77.7%] versus 1173 survivors [75.6%]; p = 0.1744) was similar before and after blood cancer.Between diagnosis and end of treatment, losing a partner was slightly more frequent than finding a new partner (53 versus 44 patients), the difference being fully accounted for by the patient's partner's death during the treatment period (9 patients).Between the end of treatment and the time of the survey, 83 survivors lost their partner (34 partners died) and 104 previously single survivors found a partner.

Family
In 710 of 984 survivors who reported to have lived with the same partner before and after blood cancer, the relationship was described as unchanged (72.2%).209 survivors reported an improvement (21.2%) and 65 a 31 .MGUS monoclonal gammopathy of undetermined significance, MM multiple myeloma, iNHL indolent non-Hodgkin lymphoma, CLL chronic lymphocytic leukemia, MPN myeloproliferative neoplasm, CML chronic myeloid leukemia, MDS myelodysplastic syndrome, aNHL aggressive non-Hodgkin lymphoma, HL Hodgkin lymphoma, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia.a Allogeneic transplantation for MM, 9 patients; iNHL/CLL, 24; MPN/CML, 219; MDS, 40; aNHL/HL, 23; AML/ALL, 239.b Time from last treatment in 1279 survivors receiving blood cancer treatment (82.5% of total number of survivors).www.nature.com/scientificreports/deterioration (6.6%).Most survivors also had an unchanged relationship with their children.In 844 of 1054 survivors who had one or more children at the time of diagnosis, the relationship remained unchanged (80.1%), while an improvement was reported by 174 survivors (16.5%) and a deterioration by 36 (3.4%).

Employment
The time after the hematological malignancy was characterized by a statistically significant decrease in full-time employment (from 49.3 to 27.5%), with a concomitant increase in disability (from 2.2 to 7.9%) and retirement (from 15.2 to 38.1%).The decrease in full-time employment and the increase in disability and retirement were statistically significant for the entire population and the age groups between 40 and 65 years (Table 2).This was not fully accounted by the number of survivors reaching the official retirement age of 65 years, as it was also seen in younger age groups ( ) reported permanent discontinuation.The latter group had not resumed their former profession for a median time period of 9 years (IQR, 6-13) at the time of the survey.There were statistically significant differences between different age groups (Table 3).While temporary impairment was most pronounced in young patients, permanent discontinuation of vocational activities was most frequently reported by survivors age 40-49 at the time of diagnosis.

Financial situation
Financial problems resulting from blood cancer-related income reduction were reported by 377 of 1439 responding survivors (26.2%), most often in survivors age 30-39 at the time of diagnosis (Table 3).The frequency of financial problems differed significantly among disease groups (p < 0.0001).They were most frequent in survivors from the AlloTx group (37.5% [194 of 517 responding patients]), followed by MM (31.4% [11/35]  1).Findings in MGUS, MM, and MDS were based on very small numbers.Quality of life was similar among survivors followed up for 4-5, 6-10, or > 10 years (Fig. 2).

Religion
On a scale from 0 (totally unimportant) to 4 (very important), the attitude towards religion showed a statistically non-significant trend (p = 0.0649) towards greater importance immediately after blood cancer treatment and during follow-up (Table 4).

Discussion
The major results of this study are the following: first, blood cancer and its treatment appeared to have little impact on relationships with family members and friends.Second, employment was severely affected, with a substantial proportion of survivors discontinuing work permanently.Third, blood cancer-related financial problems were frequent.Fourth, quality of life differed significantly among disease groups.
In the ABC study, the proportion of married patients remained constant before and after blood cancer.In blood cancer survivors from France, Norway, and the USA, the divorce rate was slightly lower than in the general population 15,16,18 .Similar observations have been made for other types of cancer survivors 32 .The relationship with family members was described as unchanged by most ABC study participants.Improvements were reported more often than deteriorations in the relationship with children and in the relationship with partners who had witnessed the whole trajectory from blood cancer diagnosis to follow-up care at the time of the survey.This is in line with an early report on American Hodgkin lymphoma survivors where positive changes in family, friend and other were more often encountered than negative changes 19 .In the ABC study, the number of social contacts was not influenced by blood cancer.In a French study restricted to Hodgkin lymphoma, loss of a friend was less often observed in study participants than in matched controls 15 .
Almost half of the patients reported a temporary impairment of their vocational activities, with an average period off work of 11 months.This is consistent with other reports where the average time off work was 5 months for all cancer patients combined 33 , 9 months for hematological patients in general 21 , and 14 months for patients undergoing autologous blood stem cell transplantation 23 .The same is true for the observation that more than a third of ABC study participants discontinued work permanently.The proportion of patients not returning to work has been reported to be 34-36% for all cancers combined 33,34 , 23-27% for hematological cancers in general 21,27 , 40% for allogeneic transplantation 35 , and 45-50% for autologous transplantation 23,30 .In a registrybased Danish study, the return-to-work rate was high in patients with lymphoma (72-89%), intermediate in leukemia (51-76%), and low in multiple myeloma (32%) 21 .Unemployment has repeatedly been identified as a risk factor for poor quality of life 25,30,35,36 .
The proportion of blood cancer survivors receiving a disability pension was lower in the ABC study (7.9%) than in other countries.In Denmark, the disability rate was 17% for hematological patients in general 22 and 27% for patients undergoing autologous transplantation 23 .In the USA, it was 34% for all cancer patients combined 37 and 39% for allogeneic transplant recipients 35 .The discrepancies may be related to differences in health care systems, follow-up periods, patient selection, and evaluation methods (questionnaire-, interview-, or registrybased studies).Distinguishing between disability and retirement pensions may have been difficult for ABC study participants.At the time of the survey, 38.1% of survivors received a retirement pension.In Denmark, early retirement was observed more frequently among patients with leukemia and non-Hodgkin lymphoma than among most other cancer patients 24 .www.nature.com/scientificreports/More than a quarter of ABC study participants reported financial problems resulting from blood cancerrelated income reduction.The proportion was even higher among allogeneic transplant recipients and patients with relapsed disease.Our questionnaire did not allow us to specify the areas affected by financial problems.Expenditures for health care, significantly contributing to disease-related economic burden in the USA 37 , were unlikely to be of importance in ABC study participants, since in Germany the treatment costs are covered by a mandatory health insurance.For most participants, the type of insurance did not differ before and after blood cancer.In the Netherlands, financial problems were often encountered when lymphoma survivors attempted to obtain a life insurance (problems reported by 38-60% of survivors) or a property mortgage (63-73%) 28,29 .In the USA, the annual productivity loss unrelated to health care costs has been estimated to be $ 2250 for cancer patients below age 40 and $ 1018 for patients above age 40 37 .In Germany, a monthly loss of 500 € has been estimated for allogeneic transplant recipients 34 .
At a median follow-up of 9 years, quality of life was best in patients with a history of acute leukemia not treated by allogeneic transplantation.In an early interview-based investigation from the USA, acute leukemia survivors enjoyed better quality of life than Hodgkin lymphoma survivors 38 .The cure rate in acute leukemia is considerably lower than in Hodgkin lymphoma, but surviving patients are at much lower risk for late relapses, second primary malignancies, cardiovascular complications, and debilitating long-term treatment effects, such as polyneuropathy (unpublished results from the ABC study).
Unexpectedly, the worst quality-of-life scores were recorded in patients with myeloproliferative disorders.Although these diseases can only be cured by allogeneic transplantation, their prognosis is among the most favorable of all types of blood cancer.Long-term control of chronic myeloid leukemia is the rule, and the life expectancy of patients with myeloproliferative neoplasms approaches that of the general population 39 .Quality of life, however, has consistently been reported as low [40][41][42][43] .Unlike other types of blood cancer, myeloproliferative  diseases are active during the follow-up period, and, in blood cancer survivors, active disease is associated with poor quality of life 44,45 .In addition, myeloproliferative diseases harbor a small risk of transformation to an almost invariably deadly type of acute leukemia which may be perceived as a distressing prospect.Most types of myeloproliferative diseases require continuous treatment that may be poorly tolerated.The patients' major complaint, fatigue, reduces social interactions and promotes isolation 40,41,43,46,47 .Because we did not have a matched control group, we were unable to compare the quality of life of ABC study participants with that of the general population 31 .Other studies have come to the conclusion that quality of life is lower in blood cancer survivors than in non-affected controls 28,29,35,36,42,43,48 .In the ABC study, the quality of life appeared to be independent of follow-up duration which is in line with earlier observations 35,36,45,49 .Religion tended to become more important after the advent of blood cancer, although this finding did not reach statistical significance.Deepening of religious and spiritual beliefs after blood cancer treatment has previously been reported for allogeneic transplant recipients from the USA 50 .
Strengths and weaknesses of the ABC study have been discussed before 31 .In brief, limitations include participation and recall biases, inherent in any retrospective study, and a prevalence-incidence bias, i.e., restriction of the analysis to individuals alive at the time of the survey.In addition, MDS, MGUS, and MM were underrepresented 31 , precluding a meaningful comparison with other disease groups.Finally, the cross-sectional design of the ABC study prevented firm conclusions with regard to temporal changes 20 .Since the follow-up period spanned many years, the interval between the time before and after blood cancer varied from participant to participant.Restricting the study to survivors with an interval of at least 3 years since the last intense treatment, however, insured that the disease was well controlled, leaving a reasonable amount of time to adapt to the consequences of the disease and its treatment.
In conclusion, a large proportion of long-term blood cancer survivors reported a significant impairment of vocational activities, which was associated with reduced income and financial problems.Unemployment is a risk factor for poor quality of life 25,30,35,36 .Efforts should be made at an early stage to reestablish the patients' ability to work.
Figure1.Quality of life in long-term survivors of different types of blood cancer at the time of the survey, as assessed by the EORTC QLQ C-30 (global health status, functioning, symptoms) and HADS questionnaires (depression).The results of the HADS anxiety scale (not shown) were similar to those of the depression scale.MGUS monoclonal gammopathy of undetermined significance, 16 responding survivors, MM multiple myeloma, 37 survivors, iNHL/CLL indolent non-Hodgkin lymphoma/chronic lymphocytic leukemia, 254 survivors, MPN/CML myeloproliferative neoplasm/chronic myeloid leukemia, 106 survivors, MDS myelodysplastic syndrome, 5 survivors, aNHL/HL aggressive non-Hodgkin lymphoma/Hodgkin lymphoma, 481 survivors, AML/ALL acute myeloid leukemia/acute lymphoblastic leukemia, 74 survivors, AlloTx allogeneic transplantation, 547 survivors.Box, range between the 25th and 75th percentile; whiskers, upper quartile with maximum and lower quartile with minimum, respectively; horizontal line, median; diamond, mean.

Figure 2 .
Figure 2. Quality of life in long-term blood cancer survivors at the time of the survey in relation to the duration of follow-up, as assessed by the EORTC QLQ C-30 (global health status, functioning, symptoms) and HADS questionnaires (depression).The results of the HADS anxiety scale (not shown) were similar to those of the depression scale.Follow-up 4-5 years, 284 responding survivors; 6-10 years, 516 survivors; > 10 years, 720 survivors.Box, range between the 25th and 75th percentile; whiskers, upper quartile with maximum and lower quartile with minimum, respectively; horizontal line, median; diamond, mean.

Table 3 .
Impairment of vocational activities and financial problems associated with the diagnosis of blood cancer.a Age at the time of the blood cancer diagnosis.b Analysis restricted to survivors in employment at the time of the blood cancer diagnosis.c Chi 2 test, p = 0.0001 for comparison of age groups.d Chi 2 test, p = 0.0031 for comparison of age groups.e Chi 2 test, p < 0.0001 for comparison of age groups.

Table 4 .
Attitude towards religion before the diagnosis of blood cancer, at the end of treatment, and at the time of the survey in 1292 survivors evaluating all three time-points.Chi 2 test, p = 0.0649.